Clinical factors associated with successful liquid tumor biopsy in men with prostate cancer.
Authors: Aixia Guo, Luca Faustino Valle, Sara Ahmed, Kerry G. Rowe, Colin C. Pritchard, Robert Bruce Montgomery, Isla Garraway, Nicholas George Nickols, Kara Noelle Maxwell, Michael J. Kelley, Matthew Rettig
Journal: Journal of Clinical Oncology (2023)

e13567 Background: Liquid biopsies using cell-free DNA (cfDNA) can be used in prostate cancer (PrCa) patients when tissue is unavailable and repeat biopsy is not feasible. Given the older age of PrCa patients, liquid biopsy may detect alterations related to clonal hematopoiesis of indeterminate potential (CHIP), generating uncertainty in the clinical utility of the results. We sought to identify clinical predictors of successful cfDNA biopsy, where the reported alterations are more likely to reflect the individual’s prostate cancer cfDNA instead of CHIP in a large cohort of United States Veterans with PrCa. Methods: Next-generation sequencing of cfDNA biopsy specimens was performed through the VA National Precision Oncology Program (NPOP) from February 2019 to November 2022. Successful identification of PrCa cfDNA testing was defined as the identification of an alteration in one or more PrCa-related genes included on the panel ( AR, CDK12, SPOP, MED12, CCND1, BRAF, AKT1, TMPRSS2, ERG, ETV1, and ETV4). Student’s t-tests, univariate, and multivariate logistic regression estimated significant patient and disease-specific factors at the time of cfDNA biopsy and the likelihood of obtaining a successful cfDNA biopsy result. Results: Among 5611 total cfDNA tests performed, 2066 cfDNA tests from 1985 Veterans listed PrCa as the clinical indication, passed quality control measures, and could be linked to patient-level demographics. 814 (39%) tests were deemed successful based upon identification of at least one PrCa related gene alteration. The most frequently encountered PrCa alterations were in AR (76.5%) and TMPRSS2 (22.4%). PSA was significantly higher (IQR 209.1 ng/ml) and PSA doubling time (PSADT) was significantly shorter (IQR 2.4 months) in the cohort of Veterans with successful cfDNA testing (p&lt;0.001). Among 1581 tests that reported tumor fraction, an elevated tumor fraction &gt;10 was also significantly associated with success (46.3% vs 8.1%, p&lt;0.001). On multivariate analysis, PSA elevation above 4.8 ng/ml (p&lt;0.001) and PSADT &lt;6 months (p&lt;0.001) were significantly associated with successful cfDNA testing. Actionable DDR mutations, including ATM (15.2% vs 11.7%, p=0.02), BRCA1 (1.7% vs 0.6%, p=0.03), and BRCA2 (7.4% vs 4.4%, p=0.01) were significantly more likely to be detected in a successful test compared to an unsuccessful test. Conclusions: High PSA and short PSADT are significant predictors of a cfDNA test identifying PrCa-related gene alterations in Veterans with metastatic disease instead of alterations due solely to CHIP. Liquid biopsy in PrCa should be reserved for patients with relatively higher disease burden or more aggressive growth rate, reflected by PSA values &gt; 4.8 and PSADT &lt; 6 months, to increase the likelihood of identifying actionable alterations and improve interpretation of testing.